Oxy-phenyl cyclohexane-and cyclohexene-carboxylic acids and derivatives



Patented Aug. 25, 1953 OXY-PHENYIJ CYCLOHEXANE AND CYCEO- HEX'ENE GARBGXYLIC' ACIDS AND DE RIVATI VE S Ered'ericktCl Novell'msProspeot-Pank Ba .assignon to Merck Co.,. Inc.,

Jersey a. corporation .of' :New

ApplicatiomMay 10; 1951 ,-Senia:l No.= 2253484? and in which and R arelower alkyland R is chosen from the group" consisting of hydroxy; methoxy; lower acyloxy and benzoxy; and X is chosen from'the group consisting of hydrogen and lower alkyl.

The compounds of the invention are prepared according to the series of .reacti'onsas illustrated in theiflow' sheet; Thus; starting witharr appropriate 3-(p-methoxyphenyl) -6-alkyl-6-cyano'- cyclohexenJ-one l (I') ('thepreparation"ofwhich is .d'es'cribedcin my co-pending applications SerialNozZDGflfiOfiled January 18, I951, and'en titled 3- (p-substituted phenyl) --cyclohexanols')-by reaction with a Grignard reagent of" the formula RMgX thereis. produced 3- (p-methoxyphenyl) 1,G-dialkybfi-cyanocyclohexen-2 -ol-i (I I) These compounds can be dehydrated by" knownmethodstdyield' a variety of 3- (p-methoxypheny-li- 1",6 dialkyl fi cyanocyclohexadienes (III) It will be'und'erstood'that where R is a primary or secondary alkyd radical containing 2 or more carbon atoms the conjugated system may be as shown for structure H-I orit'may-he-exocyclic as in IIIa'. Upon catalytichydrogenation with palladium catalyst and acetic acid; :JIII and lIIIa are converted to '3-(p methoxyphenylfi 1;6=-dialliyI;6- cyanocyclohexanes 6W); On'the: other hand, if the catalytic hydrogenation of the: above com pounu'sis carried out with platinum; catalyst; and

.6 Claims.- (Cl. 260-420) ethylacetatetpartial reduction of the dienei takes place? and-there is obtained 3- (p methoxyphenyl) -l fi -dialleyl 6-cyanocyclohexene-2 (V), It is to =berrealizedrthat the: hydrogenation. of llIw according to thesprocedureiust described cangive rise tocyclohexenes exhibiting meta-isomerism. Hydrolysis 0f"the-nitni1e groups of the. cyclohexane -and- -cyclohexenecompounds, thus prepared, is accomplished by treatment with alcoholicrpotassium hydroxide! at elevated temperaturepthis reaction-is accompanied'by simultaneous 'demethylati'oni of: the methoxy substituent and there is thus obtained 3.-(p.-hydroxyphenyl)-- 1-,, '6=-dialky1-S-carboxycyclohexane .(VI) and: 3- (p'ashytiroxyphenyl): 1-,6 diaIkyL-S -carboxycyclohexener-a (MI-1)..

The p-methoxy=homologuesof VLand- VII. are

prepared! by methylationof these compounds with methyl sulfate and-alkalL Similarly the p-benzoxyhomolog ues are preparedby the ben. zoylat-ioniot these compounds with benzoyl chloride in pyridine. Further the p-acyloxy-homologueswa-re prepared by the acylation of the abovemompounds with acylchlorides.

Further; having:obtained-the various carboxylic acids above described; these can be esterified by reactionwithr-an appropriate alcohol accordingto known-methods.-

The compoundsof this inventionpossess estrogenic activity. l

Enrwmple 1-Ewepavation of 3- (p -hydroa:yphenyl) -fi-carboazy 1 ,6-- dimethylcyclohexana- 3 (p methoxyphenyl) -.fi --cyano 1,6 dimethyloyclohexerr- 2 -01 I wasprepared as fol.- lows: A filtered solution of methyl. magnesium iodide. in 100. ml. ether, prepared from. 2.443 grams. (Oalmole) oil-magnesium. and 14.2 grams (0.1 mole) of methyliodide, was addeddropwise with stirring over a-ltenminuteperiod to a solution of 4.8 (0.02 mole) of 3-(p-methoxyphenyD- 6-cyano B-methylcyclohexen-Z-one-1 inv 20 ml. benzene and'fillmlt ether at room. temperature. The: mixture was: refluxed for. one. and. one-half hours. .I-hemix-ture: was cooledandpoured onto aamixturei-of gramsice:and.25-ml.. dilute hy-- drochloric acid. The: organic layer was separatedz and theraqueouslayer was extracted with IOO'mI. ether and the ether extract. added. to the organic layer. The? organic layer was extracted twicewithi25imlaportions'water, one 25 ml.;portion 5% sodiumrthiosulphate.solution one 25 ml. water, one 25 m1. portion 5% sodium bicarbonate solution; and-dried over. anhydrous sodium sulphate; The sodium isulphatei was removed by filtration;- vand theaethen wasremoved. by dis: l

tillation. The residue was crystallized from ether-petroleum ether. There were obtained colorless needles of 3-(p-methoxyphenyl)-6- cyano-1,6-dimethylcyclohexen-Z-ol-1.

3 (p-methoxyphenyl) 6 cyano 1,6 dimethylcyclohexadiene-1,3 was prepared as follows: 5.0 grams (0.02 mole) of the above prepared cyclohexenol was mixed intimately with 1 gram potassium acid sulphate and the mixture was distilled in vacuo. 0.5mm. There was obtained 3.6 grams of the desired product, which was crystallized from methanol. The product was obtained as colorless needles, M. P. 87-90 C.

2.9 grams (0.012 mole) of this cyclohexadiene was dissolved in 25 ml. glacial acetic acid and shaken under an atmosphere of hydrogen at room temperature and atmospheric pressure in the presence of 150 mg. of palladium black.

When uptake of hydrogen ceased, the catalyst was removed by filtration and the filtrate concentrated to dryness in' vacuo. The residue was taken up.in 200 ml. ether. The ether solution was washed twice with 25 ml. portions water and dried over anhydrous sodium sulphate. The sodium sulphate was removed by filtration and the ether by evaporation on a steam-bath. The residue'was distilled in va-cuo, There was obtained I v 3-(p-methoxyphenyl) -6-cyano1,6-di methylcyclohexane, a colorless oil.

4.4 grams (0.02 mole) of this cyclohexane', 'gramspotassium hydroxide, and 50 ml. methanol were heated in a steel bomb at 210 C. for thirtysix hours with shaking.

The contents of the bomb were cooled and the methanol removed by evaporation to dryness.

Theresidue was taken up in 100 ml. water and acidified with dilute hydrochloric acid. There resulted a solid precipitate which was extracted with 200 ml. ether. The ether layer was washed twice with 50 ml. portions water and dried over anhydrous sodium suphate. The sodium sulphate was removed by filtration and the ether by evaporation. The residue was crystallized from benzene-hexane. There was obtained the desired product 3-(p-hydroxyphenyl) -6-carboxy- 1,6-dimethylcyclohexane M. P. 192-193 C.

Example 2-Preparation of 3-(p-hydroasyphenyl) 6 carboxy 1 ethyl 6 methylcyclohexane.-Following the procedure outlined in Example 1 and substituting for the methyl magnesium iodide there used an equimolar quantity.

of ethyl magnesium iodide there was obtained 3 (p hydroxyphenyl) 6 carboxy 1 ethyl- G-methylcyclohexane, B. P. 135-145" C. at 1 micron pressure Example 3-Preparation of B-(p-hydroxyphenyl) 6 carboxy 1,6 dimethylcyclohexene- 2.-3 (p methoxyphenyl) 6 --cyano 1,6- dimethylcyclohexadiene-1,3 (prepared as in Example l) (4.8 grams, 0.02 mole) was dissolved in 100 ml. ethyl acetate. To this mixture there was added 500 mg. Adams catalyst and the mixture was shaken under an atmosphere of hydrogen at atmospheric pressure at room temperature. When hydrogen uptake ceased, the catalyst was removed by filtration and the ethyl acetate by distillation to dryness in vacuo. The residue was distilled in vacuo yielding a pale yellow oil which was recrystallized from methanol. There was obtained colorless flakes of B-(p-methoxyphenyl)-6-cyano-1,6-dimethylcyclohexene-2, M. P. 128.5130 C. V

This cyclohexene was treated with alcoholic potassium hydroxide in a bomb as described in Example 1. There was obtained the desired 4 product 3- (p-hydroxyphenyl) -6-carboxy-1,6-dimethylcyclohexene-2.

Example 4Preparation of 3-(p-hydr0myphenyl) 6 carboxy 1 ethyl 6 methylcyclohewene-2.-Following the procedure outlined in Example 1 andsubstituting for the methyl magnesium iodide there used an equimolar quantity of ethyl magnesium iodide there was obtained a mixture of 3-(p-methoxyphenyl) -6-cyano-1-eth yl-6-methylcyclohexadiene-1,3 and 3-(p-methoxyphenyl) 6 cyano l ethylidene 6 methylcyclohexene-2. Following the hydrogenation and hydrolysis procedure outlined in Example 3, there was obtained 3-(p-hydroxyphenyl)6-carboxy-l-ethyl-6 methylcyclohexene-2.

Example 5Preparation of 3-(p-meth'oxyphenyl) 6- carboxy 1,6 dimethylcycZ0hexane.-3- (p hydroxyphenyl) 6 carboxy 1,6 dimethylcyclohexane (obtained as in Example 1) was dissolved in aqueous sodium hydroxide and the solution cooled. There was added dropwise and with stirring an equimolar quantity of dimethyl sulphate. The mixture was then heatedon a steam-bath for approximately one hour after which it was cooled and acidified with dilute hydrochloric acid. The solid precipitate was extracted with ether, the ether layer washed twice with water and dried over anhydrous sodium sulphate. The sodium sulphate was removed by filtration, the ether by evaporation to dryness and the product was recrystallized from benzenehexane. There was obtained 3-(p-methoxyphenyl) -6-6-carboxy-1,6-dimethy1cyclohexane.

Similarly, following the above procedure and starting with 3-(p-hydroxyphenyl) -6-carboxy-1- ethyl-6-methylcyclohexane (obtained as in Example 2) 3-(p-hydroxyphenyl) 6-carboXy-1,6- dimethylcyclohexene-2 (obtained as in Example 3), and 3-(p-hydroxyphenyl) -6-carboxy-l-ethyl- 6-methylcyclohexene-2 (obtained as in Example 4), there was obtained 3-(p-methoxyphenyl) 6 carboxy-1-ethyl-6-methylcyclohexane, S-(methoxyphenyl) 6 carboxy 1,6 dimethylcyclohexene-2, and 3-(p-methoxyphenyl) -6-carboxy- 1-ethyl-6-methylcyclohexene-2 respectively.

Example 6-Preparatton of 3(p-hydromyphenyl) 1 butyl v6 carboxy 6 methylcyclohexane-Followingthe procedure outlined in Example 1 and substituting for the methyl magnesium iodide there used an equimolar quantity of butyl magnesium iodide there was obtained 3 (p hydroxyphenyl) 1 butyl 6 carboxy- B-methylcyclohexane.

Example 7Preparatioh of 3-(p-hydroryphenyl) 6 carboxy 6 ethyl 1 methylcyclohexane.-3 (p hydroxyphenyl) 6 carbethoxy-6-ethyl-cyclohexene-2-one-1 was prepared as follows: 20.5 grams (0.13 mole) ethyl ethylacetoacetate in 25 ml. dry benzene was added dropwise and with stirring to a cooled suspension of 5 grams (0.13 mole) of potassium in ml. dry benzene. When all of the potassium had reacted 150 ml. dioxane was added. The solution was cooled in ice and 15 grams (0.065 mole) p-dimethylamino-p-hydroxypropiophenone hydrochloride was added. The mixture was stirred at room temperature for approximately three hours and then heated on a steam-bath for approximately three hours. The mixture was cooled in ice and treated with dry hydrogen chloride gas for approximately one-half hour. There was added 200 ml. water and the solution extracted with 500 m1. ether. The organic layer was washed twice with ml. portions water, dried over anhydrous sodium sulphate and the sodium sulphate removed by filtration. The solution was evaporated to dryness and the residue distilled in vacuo. The distillate was crystallized from acetone-petroleum ether and there was obtained the desired product.

This product was methylated by dissolving it in aqueous alkali, cooling this solution and adding thereto an equimolar quantity of dimethyl sulphate. The product was obtained by extraction with ether and removal of the ether by evaporation, and crystallization from acetonepetroleum ether. There was obtained 3-(pmethoxyphenyl) 6 carbethoxy 6 ethylcyclohexene-Z-one-l.

Using this cyclohexenone as a starting material and following the procedure outlined in Example 1 there was obtained the desired product 3 (p hydroxyphenyl) 6 carboxy 6 ethyll-methylcyclohexane.

Similarly, by variation of the active methylene compound (1. e. ethyl ethylacetoacetate above) and using the thus obtained cyc1ohexene-2-one- 1 in the foregoing examples there are obtained a variety of 3-(p-hydroxypheny1- and 3-(pmethoxyphenyl) 6 carboxy 1,6 dialkylcyclohexanes and -cyc1ohexane-2s.

For example, 3- (p-methoxyphenyl) -6-carboxy 1-ethyl-6-isopropy1cyclohexane was prepared by using ethyl isopropylacetate in place of the ethyl ethylacetoacetate above described and following the procedure outlined in Example 5.

Example 8Preparatz'on of 3 (p hydrol'cyphenyl) 6 carbomethoscy 1,6 dimethylcyclohexane-3 (p hydroxyphenyl) 6 carboxy- LS-dimethylcyclohexane (obtained as in Example 1) was treated with acetic anhydride containing one drop of concentrated sulfuric acid. From this mixture there was obtained 3-(p-acetoxyphenyl) 6 carboxy 1,6 dimethylcyclohexane which was treated with an ethereal solution of diazomethane. When nitrogen evolution ceased, the solution was evaporated to dryness and the residue hydrolized with aqueous sodium hydroxide. The alkaline solution was acidified with dilute hydrochloric acid and the resulting precipitates taken up in an equal volume of ether. The ethereal solution was evaporated to dryness and the residue crystallized from acetone-petroleum ether. There was obtained the desired product 3-(p-hydroxyphenyl)-6-carbomethoxy-1,6-dimethylcyclohexane.

Similarly, the various 3-(p-hydroxyphenyl) -6- carboXy-l,G-dialkylcyclohexanes and -cyclohexene-2s above described can be esterified by this procedure. Thus, diazomethane will yield the methyl ester and diazoethane the ethyl ester.

C0 OX and CO OX in which R and R." are lower alkyl, R is chosen from the class consisting of hydroxy, methoxy, benzoxy and lower acyloxy; and X is chosen from the group consisting of hydrogen and lower alkyl.

2. 3 (p hydroxyphenyl) 6 carboxy 1,6- dimethylcyclohexane.

3. 3 (p hydroxyphenyl) 6 carboxy 1- ethyl-G-methylcyclohexane.

4. 3 (p hydroxyphenyl) 6 carboxy 1,6- dimethylcyclohexene-Z.

5. 3 (p hydroxyphenyl) 6 carboxy 1- ethyl-6-methylcyclohexene-2.

6. 3 (p methoxyphenyl) 6 carboxy 1- ethyl-G-methylcyclohexane.

FREDERICK C. NOVELLO'.

Name Date Natelson et a1 Jan. 31, 1950 Hogg et a1 Jan. 15, 1952 OTHER REFERENCES Rubin et al., Chem. Abstracts, vol. 40, p. 2118 (1946).

Number 

1. A COMPOUND CHOSEN FROM THE CLASS CONSISTING OF 